Racial Differences and Injury Pattern Variation: Impact of COVID-19 on a Bronx Trauma Center.

BACKGROUND: New York City (NYC) became the epicenter of the COVID-19 pandemic in 2020. The Bronx, with the highest rates of poverty and violent crime of all NYC boroughs and a large Black and Hispanic population, was at increased risk of COVID-19 and its sequelae. We aimed to identify temporal associations among COVID-19 and trauma admission volume, demographics, and mechanism of injury (MOI). METHODS: A retrospective review of prospectively collected data was conducted from a Level II trauma center in the Bronx. January 1st-September 30th for both 2019 (Pre-COVID) and 2020 (COVID) were compared. Pre-COVID and COVID cohorts were subdivided into EARLY (March-May) and LATE (June-September) subgroups. Demographics and trauma outcomes were compared. RESULTS: Trauma admissions were similar between Pre-COVID and COVID. During COVID, there was an increased percentage of Black patients (Black Hispanic 20.1% vs 15.2% and Black Non-Hispanic 39.4% vs 34.1%, P < .05), younger patients (26-35 years old: 22.6% vs 17.6%, P < .05), and out-of-pocket payors (6.0% vs 1.6%, P < .05). Trauma severity outcomes were mixed-some measures supported increased severity; others showed no difference or decreased severity. During COVID, there was a rise in total penetrating injuries (27.4% vs 20.8%, P < .05), MVC (13.2% vs 7.1, P < .05), and firearm injuries (11.6% vs 6.0%, P < .05). Additionally, during LATE COVID, there was a resurgence of total penetrating, total blunt, MVC, falls, cyclists/pedestrians struck, and firearm injuries. DISCUSSION: Our results emphasize MOI variations and racial differences of trauma admissions to a Level II trauma center in the Bronx during COVID-19. These findings may help trauma centers plan during pandemics and encourage outreach between trauma centers and community level organizations following future healthcare disasters.

A phenotypic signature that identifies neoantigen-reactive T cells in fresh human lung cancers.

A common theme across multiple successful immunotherapies for cancer is the recognition of tumor-specific mutations (neoantigens) by T cells. The rapid discovery of such antigen responses could lead to improved therapies through the adoptive transfer of T cells engineered to express neoantigen-reactive T cell receptors (TCRs). Here, through CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) and TCR-seq of non-small cell lung cancer (NSCLC) tumor-infiltrating lymphocytes (TILs), we develop a neoantigen-reactive T cell signature based on clonotype frequency and CD39 protein and CXCL13 mRNA expression. Screening of TCRs selected by the signature allows us to identify neoantigen-reactive TCRs with a success rate of 45% for CD8+ and 66% for CD4+ T cells. Because of the small number of samples analyzed (4 patients), generalizability remains to be tested. However, this approach can enable the quick identification of neoantigen-reactive TCRs and expedite the engineering of personalized neoantigen-reactive T cells for therapy.

Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers.

The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge for the engineering of cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures of CD8+ and CD4+ neoantigen-reactive tumor-infiltrating lymphocytes (TILs). Neoantigen-specific TILs exhibited tumor-specific expansion with dysfunctional phenotypes, distinct from blood-emigrant bystanders and regulatory TILs. Prospective prediction and testing of 73 NeoTCR signature-derived clonotypes demonstrated that half of the tested TCRs recognized tumor antigens or autologous tumors. NeoTCR signatures identified TCRs that target driver neoantigens and nonmutated viral or tumor-associated antigens, suggesting a common metastatic TIL exhaustion program. NeoTCR signatures delineate the landscape of TILs across metastatic tumors, enabling successful TCR prediction based purely on TIL transcriptomic states for use in cancer immunotherapy.

A machine learning model for ranking candidate HLA class I neoantigens based on known neoepitopes from multiple human tumor types.

Tumor neoepitopes presented by major histocompatibility complex (MHC) class I are recognized by tumor-infiltrating lymphocytes (TIL) and are targeted by adoptive T-cell therapies. Identifying which mutant neoepitopes from tumor cells are capable of recognition by T cells can assist in the development of tumor-specific, cell-based therapies and can shed light on antitumor responses. Here, we generate a ranking algorithm for class I candidate neoepitopes by using next-generation sequencing data and a dataset of 185 neoepitopes that are recognized by HLA class I-restricted TIL from individuals with metastatic cancer. Random forest model analysis showed that the inclusion of multiple factors impacting epitope presentation and recognition increased output sensitivity and specificity compared to the use of predicted HLA binding alone. The ranking score output provides a set of class I candidate neoantigens that may serve as therapeutic targets and provides a tool to facilitate in vitro and in vivo studies aimed at the development of more effective immunotherapies.

A systematic review of post-harvest interventions for Vibrio parahaemolyticus in raw oysters.

BACKGROUND: Non-cholera Vibrio bacteria are a major cause of foodborne illness in the United States. Raw oysters are commonly implicated in gastroenteritis caused by pathogenic Vibrio parahaemolyticus. In response to outbreaks in 1997-1998, the US Food and Drug Administration developed a nation-wide quantitative microbial risk assessment (QMRA) of V. parahaemolyticus in raw oysters in 2005. The QMRA identified information gaps that new research may address. Incidence of sporadic V. parahaemolyticus illness has recently increased and, as oyster consumption increases and sea temperatures rise, V. parahaemolyticus outbreaks may become more frequent, posing health concerns. Updated and region-specific QMRAs will improve the accuracy and precision of risk of infection estimates. OBJECTIVES: We identify research to support an updated QMRA of V. parahaemolyticus from oysters harvested in Chesapeake Bay and Puget Sound, focusing on observational and experimental research on post-harvest practices (PHPs) published from 2004 to 2019. METHODS: A predefined search strategy was applied to PubMed, Embase, Scopus, Science.gov, NAL Agricola, and Google Scholar. Study eligibility criteria were defined using a population, intervention, comparator, and outcome statement. Reviewers independently coded abstracts for inclusion/exclusion using predefined criteria. Data were extracted and study quality and relevance evaluated based on published guidance for food safety risk assessments. Findings were synthesized using a weight of evidence approach. RESULTS: Of 12,174 articles retrieved, 93 were included for full-text review. Twenty-seven studies were found to be high quality and high relevance, including studies on cold storage, high hydrostatic pressure, depuration, and disinfectant, and other PHPs. High hydrostatic pressure consistently emerged as the most effective PHP in reducing abundance of V. parahaemolyticus. DISCUSSION: Limitations of the knowledge base and review approach involve the type and quantity of data reported. Future research should focus on PHPs for which few or no high quality and high relevance studies exist, such as irradiation and relaying.

Antigen Experienced T Cells from Peripheral Blood Recognize p53 Neoantigens.

PURPOSE: The purpose of this study was to evaluate antigen experienced T cells in peripheral blood lymphocytes (PBL) for responses to p53 neoantigens. EXPERIMENTAL DESIGN: PBLs from patients with a mutated TP53 tumor were sorted for antigen-experienced T cells and in vitro stimulation (IVS) was performed with p53 neoantigens. The IVS cultures were stimulated with antigen-presenting cells expressing p53 neoantigens, enriched for 41BB/OX40 and grown with rapid expansion protocol. RESULTS: T-cell responses were not observed in the PBLs of 4 patients who did not have tumor-infiltrating lymphocyte (TIL) responses to mutated TP53. In contrast, 5 patients with TIL responses to mutated TP53 also had similar T-cell responses in their PBLs, indicating that the PBLs and TILs were congruent in p53 neoantigen reactivity. CD4+ and CD8+ T cells were specific for p53R175H, p53Y220C, or p53R248W neoantigens, including a 78% reactive T-cell culture against p53R175H and HLA-A*02:01. Tracking TCRB clonotypes (clonality, top ranked, and TP53 mutation-specific) supported the enrichment of p53 neoantigen-reactive T cells from PBLs. The same T-cell receptor (TCR) from the TIL was found in the IVS cultures in three cases and multiple unique TCRs were found in another patient. TP53 mutation-specific T cells also recognized tumor cell lines bearing the appropriate human leukocyte antigen restriction element and TP53 mutation, indicating these T cells could recognize processed and presented p53 neoantigens. CONCLUSIONS: PBL was a noninvasive source of T cells targeting TP53 mutations for cell therapy and can provide a window into intratumoral p53 neoantigen immune responses.See related commentary by Olivera et al., p. 1203.

Immunologic Recognition of a Shared p53 Mutated Neoantigen in a Patient with Metastatic Colorectal Cancer.

Adoptive cell therapy (ACT) with T cells targeting neoantigens can mediate durable responses in patients with metastatic cancer. Cell therapies targeting common shared antigens for epithelial cancers are not yet broadly available. Here, we report the identification and characterization in one patient of T-cell receptors (TCRs) recognizing mutated p53 p.R175H, which is shared among a subset of patients with cancer. Tumor-infiltrating lymphocytes were screened for recognition of mutated neoantigens in a patient with metastatic colorectal cancer. HLA-A*0201-restricted recognition of mutated p53 p.R175H was identified, and the minimal peptide epitope was HMTEVVRHC. Reactive T cells were isolated by tetramer sorting, and three TCRs were identified. These TCRs mediated recognition of commercially available ovarian cancer, uterine carcinoma, and myeloma cell lines, as well as an NIH patient-derived esophageal adenocarcinoma line that endogenously expressed p53 p.R175H and HLA-A*0201. They also mediated recognition of p53 p.R175H+ colon, breast, and leukemia cell lines after transduction with a retrovirus encoding HLA-A*0201. This work demonstrates that common shared mutated epitopes such as those found in p53 can elicit immunogenic responses and that the application of ACT may be extended to patients with any cancer histology that expresses both HLA-A*0201 and the p53 p.R175H mutation.

Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers.

Immunotherapies can mediate regression of human tumors with high mutation rates, but responses are rarely observed in patients with common epithelial cancers. This raises the question of whether patients with these common cancers harbor T lymphocytes that recognize mutant proteins expressed by autologous tumors that may represent ideal targets for immunotherapy. Using high-throughput immunologic screening of mutant gene products identified via whole-exome sequencing, we identified neoantigen-reactive tumor-infiltrating lymphocytes (TIL) from 62 of 75 (83%) patients with common gastrointestinal cancers. In total, 124 neoantigen-reactive TIL populations were identified, and all but one of the neoantigenic determinants were unique. The results of in vitro T-cell recognition assays demonstrated that 1.6% of the gene products encoded by somatic nonsynonymous mutations were immunogenic. These findings demonstrate that the majority of common epithelial cancers elicit immune recognition and open possibilities for cell-based immunotherapies for patients bearing these cancers. SIGNIFICANCE: TILs cultured from 62 of 75 (83%) patients with gastrointestinal cancers recognized neoantigens encoded by 1.6% of somatic mutations expressed by autologous tumor cells, and 99% of the neoantigenic determinants appeared to be unique and not shared between patients.This article is highlighted in the In This Issue feature, p. 983.